The present invention relates to the field of breath test instrumentation and methods of use, especially in relation to their accuracy, reliability and speed.
Gas analyzers are used for many measurement and monitoring functions in science, industry and medicine. In particular, gas spectrometry is becoming widely used in diagnostic instrumentation based on the use of breath tests for detecting a number of medical conditions present in patients. Descriptions of much breath test methodology and instrumentation are disclosed in PCT Publication No. WO99/12471, entitled xe2x80x9cBreath Test Analyzerxe2x80x9d by D. Katzman and E. Carlebach, some of the inventors in the present application. Methods of constructing and operating gas analyzers such as are used in breath test instrumentation are disclosed in PCT Publication No. WO99/14576, entitled xe2x80x9cIsotopic Gas Analyzerxe2x80x9d by I. Ben-Oren, L. Coleman, E. Carlebach, B. Giron and G. Levitsky, some of the inventors in the present application. Applications of some breath tests for detecting specific medical conditions are contained in patents issued to one of the inventors of the present application, namely U.S. Pat. No. 5,962,335 to D. Katzman on xe2x80x9cBreath Test for Detection of Drug Metabolismxe2x80x9d, and U.S. Pat. No. 5,944,670 to D. Katzman on xe2x80x9cBreath test for the Detection of Bacterial Infectionxe2x80x9d, and in allowed U.S. patent application Ser. No. 08/805415 now U.S. Pat. No. 6,067,989, by D. Katzman on xe2x80x9cBreath test for the Diagnosis of Helicobacter Pylori Infection in the Gastrointestinal Tractxe2x80x9d. Each of the above documents is hereby incorporated by reference in its entirety.
Such breath tests are based on the ingestion of a marker substrate, which is cleaved by the specific bacteria or enzymic action being sought, or as a result of the metabolic function being tested, to produce marked by-products. These by-products are absorbed in the blood stream, and are exhaled in the patient""s breath, where they are detected by means of the gas analyzer.
One well known method of marking such substrates is by substituting one of its component atoms with an isotopically enriched atom. Such substrates and their by-products are commonly called isotopically labeled. One atom commonly used in such test procedures is the non-radioactive carbon-13 atom, present in a ratio of about 1.1% of naturally occurring carbon. Using 13C as the tracer, the cleavage product produced in many such tests is 13CO2, which is absorbed in the bloodstream and exhaled in the patient""s breath. The breath sample is analyzed, before and after taking this marker substrate, typically in a mass spectrometer or a non-dispersive infra-red spectrometer. Detected changes in the ratio of 13CO2 to 12CO2 may be used to provide information about the presence of the specific bacteria or enzymic action being sought, or as a measure of the metabolic function being tested.
Since the amount of CO2 arising from the process under test may be a very small proportion of the total CO2 production from all of the bodies"" metabolic processes, the breath test instrumentation must be capable of detecting very small changes in the naturally occurring percentage of 13CO2 in the patient""s breath. Typically, the instrument should be capable of detecting changes of a few parts per million in the level of 13CO2 in the patient""s exhaled breath, where the whole 13CO2 content in the patient""s exhaled breath is only of the order of a few hundred ppm. For this reason, the sensitivity, selectivity and stability of the gas analyzers used in such tests must be of the highest possible level to enable accurate and speedy results to be obtained.
Furthermore, since the instrument is intended to operate in a point-of-care environment, where there is generally no continuous technician presence, the instrument must have good self-diagnostic capabilities, to define whether it is in good operating condition and fit for use. For similar reasons, it should also have a level of self calibration capability, to correct any drift in calibration level revealed in such self-diagnostic tests or otherwise.
The use of the instrument in a point-of-care environment adds additional importance to the speed with which an accurate diagnosis can be given to the patient following the test. Consequently, to increase patient compliance, the methods used in the breath test for analyzing the results of the measurements in terms of meaningful diagnostic information should be designed to provide as conclusive and reliable a result in as short a time as possible. Furthermore, the execution of the test in the physician""s office is greatly facilitated by the use of simple patient and substrate preparation procedures.
In order to maintain the reliability of such tests, it is necessary to ensure that the calibration of the gas analyzer is maintained at the correct level. For this reason, in order to ensure maintenance of the high accuracy levels required, many of the prior art instruments necessitate the performance of complex and time-consuming calibration procedures, some of which have to be laboratory performed, rather than user-performed in the field. Since the advent of compact and low cost breath test instrumentation is making breath testing a widely used medical office procedure, instead of a hospital or laboratory procedure, the need for simple, user-performed, periodic calibration checks is becoming of prime importance.
Furthermore, the breath exhaled by patients always contains a naturally high level of humidity, and in the case of intubated patients, could also contain a high level of moisture and other secretions. The presence of such extraneous fluids can severely affect the ability of the gas analyzer to accurately measure the sought-after gas. Furthermore, constant exposure to high levels of humidity can have an adverse effect on the component parts of the gas analyzer, and especially on the measuring sensor itself. For these reasons, moisture and humidity filters are advisable to maintain the accuracy of the instrument. Since the operator may have a tendency to use the filters provided with the instrument beyond the recommended number of times, thereby impairing the accuracy of the measurement, it is important that means be adopted to ensure that the filtration unit is not used beyond its stated lifetime.
There therefore exists a need to ensure the maintenance of the accuracy of breath test instrumentation, both by means of regular mandated calibration checks, and by ensuring regular mandated changes of the moisture filter used with the instrument. Furthermore, there is a need for the calibration check procedure to be capable of simple and preferably semi-automatic execution by the user, rather than requiring the intervention of a technician, or shipment to a calibration laboratory.
The unique characteristics of the breath test analyzer described in the above mentioned PCT Publication No. WO 99/12471, are due in large measure to the use of electrode-less cold gas discharge infra-red lamp sources, as described in U.S. Pat. No. 5,300,859, entitled xe2x80x9cIR-Radiation Source and Method for Producing Samexe2x80x9d to S. Yatsiv et al., hereby incorporated by reference in its entirety. One of the important advantages of such lamp sources is that they emit very narrow spectral lines at discrete frequencies characteristic of the molecular rotational-vibrational to ground state transitions of the excited gas species contained in the lamp. This is achieved in a source which is sealed-off, is compact, has a good level of conversion efficiency from electrical to optical power, and has a long life compared with previously available sealed-off lamps sources.
The unique spectral properties and the narrowness of the emission lines of such lamps provides such gas analyzers with high levels of selectivity, sensitivity and stability, which are many times better than gas analyzers of similar complexity, which use lamp sources of alternative technologies, such as hot blackbody sources. The other advantages mentioned above enable the production of compact and cost effective instrumentation using such sources.
The lamp sources described in U.S. Pat. No. 5,300,859 have found particularly advantageous applications as sources of the CO2 spectral emission lines, for gas analysis of exhaled breath, to determine the levels of CO2 therein. Such CO2 sources have been used to great advantage in capnography and breath testing instrumentation.
In U.S. Pat. No. 5,300,859, there is a thorough discussion regarding the parameters affecting the lamp emission rise and decay time, efficiency, excitation and output, and the lamp lifetime as a function of chemical methods used to clean the lamp before sealing. On the other hand, the question of the spectral stability of the lamp source is not addressed. However, when used as a frequency selective source in NDIR spectroscopic applications, spectral stability may even be more important than the above parameters. Intensity changes over time can easily be monitored and corrected by using a reference path, since lamp intensity is a single valued quantity. On the other hand, spectral changes can not be easily monitored or corrected for, because of the huge amount of information contained in a spectrum. Changes in the lamp spectrum cause changes in the absorption cell absorption characteristics. If these changes are not known, then it is impossible to accurately measure gas concentrations using such lamp sources. There therefore exists a serious need for a method of maintaining a high level of spectral stability in electrode-less cold gas discharge infra-red lamp sources. A high level of spectral stability would make an important contribution to the maintenance of accurate calibration levels in breath test instruments using such lamps.
The disclosures of all publications mentioned in this section and in the other sections of the specification, are hereby incorporated by reference, each in its entirety.
The present invention seeks to provide new methods and devices for ensuring the accuracy, speed and reliability of breath tests. A number of separate aspects of the invention are disclosed herein, including but not limited to subjects related to:
(i) system checking devices and methods of ensuring their periodic use;
(ii) methods of patient preparation and substrate ingestion;
(iii) methods of analysis of the results of breath tests to provide accurate diagnoses in the minimum possible time;
(iv) self-diagnostic facilities and calibration of breath test instruments; and
(v) the spectral stability for electrode-less cold gas discharge infra-red lamps, such as those used in NDIR gas spectrometers typically used in breath testers.
The term xe2x80x9csystem checkxe2x80x9d is generally used throughout this specification and claimed, to describe methods for determining that multiple aspects of the measurement system are functioning correctly, including primarily calibration of the gas analyzer, but also possibly including such functions as the radiation source stability, the input capnograph calibration, the gas handling system, the intermediate chamber system for collecting and diluting accumulated breath samples, and the detector operation.
The term xe2x80x9ccalibration checkxe2x80x9d is generally used in this specification and claimed, to refer to a measurement of the absolute calibration of the isotopic ratios measured by the breath tester, referred to a zero base line level, by the use of calibration checking gases with known isotopic concentrations or ratios, input to the instrument from externally supplied containers. Since a calibration check is part of a system check, overlapping use of these terms may have been made on occasion, according to the context under discussion.
The use of the term xe2x80x9ccalibrationxe2x80x9d of the instrument, on the other hand, is generally used in this specification and claimed, to describe a process whereby the parameters of the absorption curves used for the infra-red absorption measurements of the gases are corrected so that they compensate for drift or other environmentally induced changes occurring in the instrument. Changes in the absorption curves are indeed generally the major cause for changes in the calibration of the instrument. According to this nomenclature, a calibration procedure, as opposed to a calibration checking procedure, does not use externally supplied gases with known isotopic concentrations or ratios, but typically relies on checks for internal inconsistency in the results obtained in actual measurements performed by the breath tester. The usual inconsistency revealed is an unjustified correlation of measured values of isotopic ratio with gas concentration, as will be further expounded hereinunder.
The present invention first of all seeks to provide a new system checking device for use with gas analyzer-based breath test instrumentation, including the ability to perform a calibration check of the instrument against known calibrating gases. The use of the device with breath tests is particularly important, because of the high sensitivity, selectivity and accuracy, which must be maintained to ensure the success of such tests. The use of the device is simple, and ensures that the overall functionality and accuracy of the gas analyzer is checked at regular predetermined periods, without the need for the operator to perform complex calibration procedures. At the same time, the calibration checking device may also comprise a fluid filter, and is so constructed that its use ensures efficient fluid filtering.
There is thus provided in accordance with a preferred embodiment of the present invention, a calibration checking sampling line unit with a built-in filter, particularly for use with breath test instrumentation. In order to maintain the guaranteed accuracy of the breath test, it is important both to perform regular calibration checks of the gas monitor, and to ensure that the humidity level of the sampled gas is kept below a specified level, and that there is no liquid penetration into the gas analyzer. Each calibration check device is designed to be used for a predetermined number of tests, with a separate disposable oral/nasal part for each individual test performed. After first connection of a new calibration check device, according to one preferred embodiment of the present invention, a volume of known calibration checking gas is released into the instrument, and a calibration checking measurement is initiated. At the same time, a signal is sent to a counting mechanism which both enables the use of the instrument, and commences a count of the number of tests performed by the breath tester. The counting mechanism can be located either on the calibration checking device or in the instrument itself. When the predetermined number of tests have been performed, after which a new calibration check is recommended, the counting mechanism provides operator warning thereof, or preferably even prevents continued operation of the instrument until a new calibration check is performed. A preferred method for performing this control function is disclosed in a further embodiment of the present invention.
According to another preferred embodiment of the present invention, the signal transmitted after first connection of a new calibration check device and performance of a calibration check procedure, is sent to a timing mechanism which both enables the use of the instrument, and begins accumulating the amount of time that the breath tester has been in operation since the last calibration checking procedure. When a predetermined operation time has been exceeded, after which a new calibration check is recommended, the timer mechanism provides operator warning thereof, or preferably even prevents continued operation of the instrument until a new calibration check is performed.
According to a further preferred embodiment of the present invention, the built-in moisture filter also has an interface with the instrument, which prevents its operation if the filter is used beyond the recommended number of times, or if excess moisture renders it saturated. As an alternative to a multiple-use filter unit, the disposable oral/nasal part supplied for each individual test could be provided with a built-in section of moisture filtering or moisture absorbing material, to ensure the use a fresh filter element for every patient test. According to this embodiment of the invention, the use of a fresh filter, while not mandated, should be performed automatically if normal hygienic clinical procedures of using a new cannula for every test are followed. In this case, to give additional assurance that a new cannula would be used for every test, each calibration check unit is preferably supplied as a kit with the number of disposable oral/nasal parts, which would suffice for the number of tests expected to be performed within the recommended changing period of the calibration check unit.
In accordance with further preferred embodiments of the present invention, where the particular circumstances of the test conditions allow it, the calibration check device can incorporate a calibration check unit only, without a filter device, or a filter device only, without any calibration check unit. Alternatively and preferably, the calibration check device can contain both a calibration check unit and a filter unit, and the enable or count signal transmitted to the instrument from only one or other of the two units.
According to further preferred embodiments of this aspect of the present invention, the calibration checking device is used in co-operation with a breath simulating device inside the breath tester, the combination operating as a complete system checking device. From the calibration checking device gas fill, a series of gas samples is produced which simulate all aspects of the breath of a subject undergoing a breath test. According to these embodiments, the breath simulator provides samples of (i) ambient air with the natural level of the breath test gas, to simulate the inhaled breath, (ii) a sample of the gas to be detected in the breath test with a known low isotopic ratio, to simulate the exhaled breath of a subject before ingestion of the isotopically labeled substrate, and (iii) a sample of the breath test gas having an isotopic ratio of the detected component somewhat increased, to simulate the exhaled breath of a subject having a detectable response to the breath test. The timing of the supply of these three types of calibration check input gases is preferentially provided by means of a pneumatic system using solenoid valves to route the gases through the correct paths, and at the correct timing rate to simulate human respiration rate. According to alternative preferred embodiments, the calibration checking gas with the slightly raised isotopic ratio component is generated either by means of a porous tube device, able to preferentially change the isotopic content of a gas flowing through it, or by means of two separate calibration checking gas containers, each containing a gas fill with a slightly different isotopic ratio.
According to a second aspect of the present invention, there is provided in accordance with further preferred embodiments of the present invention, methods relating to the patient preparation before administration of the breath test. These methods are made possible only because of the method of virtually continuous sampling and analyzing of breaths, as described in this application, and in the documents described in the background section. In addition, methods of preparation and administration of the substrate for ingestion before the breath test are described.
It is to be understood that, throughout this specification and as claimed, the use of terms to describe sampling and/or analyzing, such as xe2x80x9cvirtually continuous samplingxe2x80x9d or xe2x80x9cvirtually continuous analyzingxe2x80x9d or equivalent descriptive expressions, such as xe2x80x9csubstantially continuouslyxe2x80x9d, are meant to refer to methods of sampling or analyzing capable of being performed repeatedly and repetitively at a rate which is sufficiently high that a number of samplings and/or analyses are performed within the time taken for useful clinical information to be determined from the physiological effects under investigation by the breath test. This rate is thus highly dependent on the type of breath test involved. In the case of a breath test such as that for the detection of Helicobacter pylori, for instance, where a meaningful clinical result may already be obtained in a matter of a few minutes, xe2x80x9cvirtually continuous samplingxe2x80x9d could be taken to mean a rate as fast as almost every exhaled breath of the subject. On the other hand, with breath tests such as that for liver function, in which it could be several hours before a meaningful result is obtained, the condition of xe2x80x9cvirtually continuous samplingxe2x80x9d or equivalent terms, may be fulfilled by means of a breath sample collection and/or analysis every half hour, for instance.
It is this feature of virtually continuous sampling or analysis which provides the present invention with many of its advantages over prior art methods of sampling and analyzing individual bags of breath. From a practical point of view, it is difficult, if not well-nigh impossible, to perform such prior art methods xe2x80x9cvirtually continuouslyxe2x80x9d, and it is this feature which thereby enables the present invention to provide clinically significant results both earlier and with a higher level of reliability than by prior art methods.
According to a third aspect of the present invention, there are also provided in accordance with more preferred embodiments of the present invention, methods for analysis of the results of breath tests to provide accurate diagnoses within times significantly shorter than those possible by use of prior art methods. These methods include the use of a method for detecting the presence of oral activity in the subject, arising from the direct interaction of the labeled substrate with bacteria in the oral cavity, unrelated to the physiological state being tested for. It is important to detect such oral activity, and to delay the analysis of the collected breaths until after its subsidence. Otherwise the breath test""s ability to detect by-products of the labeled substrate exhaled in the subject""s breath after traversing a metabolic path through the subject""s blood stream and lungs, would be severely degraded.
Further novel methods are disclosed for calculating the change in isotopic ratio over the baseline isotopic ratio, which enable more reliable test results to be obtained in situations where there may be interference or excessive noise in the measurement. A further method is described for combating the effects of drift in the breath test instrumentation, which may limit the ability to accurately compare currently collected samples with a baseline sample collected earlier. According to this preferred embodiment of the present invention, the sample collected at each sampling point is compared with the sample collected at the previous sampling point, rather than with a baseline sample or an external reference gas.
Further preferred embodiments are disclosed in which the changes in isotopic ratio detected are analyzed using a newly proposed parameter, called the Relative Change in Isotopic Ratio, or RCIR, which compares the fractional change in the currently obtained ratio, normalized to a variety of isotopic ratios, each of which has its own specific advantages. A method is also disclosed of using alternating definitions for the RCIR parameter, according to the progress of the test results, in order to reduce the effects of physiological or instrumental noise in the test results. A method for more accurate detection of the baseline level is also disclosed, whereby multiple baseline measurements are made to eliminate the possible negative effects of a single rogue measurement point.
The operational function in a breath test is to determine when a change in the isotopic ratio of a component of breath samples of the subject is clinically significant with respect to the effect being sought. The criterion for this determination, as used in much of the prior art, is whether or not the isotopic ratio has exceeded a predefined threshold level, at, or within the allotted time for the test. According to another preferred embodiment of the present invention, in order to achieve the highest sensitivity and specificity in the shortest possible measurement time, the breath test analyzer does not use fixed criteria for determining whether the change in the isotopic ratio of a patient""s breath is clinically significant. Instead, the criterion is varied during the course of the test, according to a number of factors manifested during the test, including, for instance, the elapsed time of the test, the noise level of the instrument performing the test, and the physiological results of the test itself.
Furthermore, although in many of the prior art procedures, the measurement used for the change in the isotopic ratio has been the level of the ratio over a baseline level, according to further preferred embodiments of the present invention, the measurement could be the change over a previous measurement point other than a baseline level, or the rate of change of the isotopic level, or any other suitable property which can be used to plot the course of the change.
As an example of the execution of such a variable criterion, the crossing of a threshold level by the isotopic ratio is used to illustrate the advantages of these preferred embodiments of the present invention. A calculation method is disclosed for the more accurate use of the threshold level, above which, according to the methods of the prior art, a test result is assumed to be positive, or below which it is assumed to be negative. The method makes use of a dynamically variable threshold, whose value changes according to the progress of the breath test. It is optionally and preferably made dependent on the elapsed time of the test, on the physiological meaning of the results, on the scatter or quality of the results themselves, and on the noise level or drift of the instrument being used. In addition, further preferred embodiments using multiple thresholds are disclosed.
According to a fourth aspect of the present invention, there are also provided, in accordance with other preferred embodiments of the present invention, methods for self-diagnostic analysis of a breath test instrument, and for system checking of the instrument. According to these preferred embodiments, novel methods are disclosed for calibration of the instrument according to the data being collected, either automatically, or by means of operator intervention. Such methods generally are based on the assumption that if the absorption curve of the gas analyzer is accurately known, then the isotopic ratio measured in the gas being detected, according to the supposedly correct absorption curve, will show no dependence on changes in the concentration of the sample being measured. Any such dependence found is reduced by means of an iterative correction method, which changes the parameters of the absorption curve in such a manner as to reduce any such correlation.
Another preferred method disclosed according to this aspect of the present invention is operative for correcting any inaccuracy in the capnographic measurement performed at the entrance to a breath tester, by means of comparison with an accurate measurement performed by the self-calibrating gas analyzer, as summarized above. The capnographic measurement is used in order to determine which parts of the breath waveform are collected for analysis by the gas analyzer in the breath tester.
According to a fifth aspect of the present invention, there is provided, in accordance with another preferred embodiment of the present invention, a new method of producing cold gas discharge infra-red lamp sources with improved spectral stability, especially for those lamps operating with a carbon dioxide fill. A catalyst is used to induce recombination of the dissociation products of molecules of the fill gas broken down by the action of the electrical discharge, and the resulting maintenance of the level of self absorption of the lamp emission, results in a concomitant maintenance of the spectral shape of the lamp emission. As a result of this maintained spectral purity, a breath tester utilizing such a lamp has improved resolution and improved accuracy, resulting from the more accurate and better resolved absorption measurement made on the isotopic gas mixture.